While therapy for good-prognosis head and neck cancer (HNC) achieves a high rate of cure, current therapy for poor prognosis HNC such as non-resectable cancer is unsatisfactory with local-regional (LR) control rates around 50% after chemo-irradiation, representing the major failure pattern in these patients. Multiple studies have demonstrated that lack of tumor perfusion observed by dynamic contrast-enhanced MRI (DCE-MRI), and low diffusion observed on diffusion-weighed MRI (DW-MRI), representing both lack of tumor membrane disruption and high tumor cellularity, are each associated with higher rates of LR failure rates following therapy. We propose to use these functional imaging modalities to guide intensifying of radiotherapy to tumor sub-volumes predicted to be resistant to therapy, in order to overcome resistance and improve LR tumor control, which will improve disease-free and potentially overall survival in these patients. Aim 1 is to conduct a randomized phase II study comparing intensification of the radiation doses to the tumor sub-volumes demonstrating poor perfusion early after the start of chemo-radiation. Aim 2 is to investigate the optimal integration of DW-MRI with DCE-MRI in determining the resistant tumor sub-volumes, and Aim 3 is to investigate functional MRI as a predictor of late damage of the swallowing organs, in order to individualize the sparing of these organs aiming to reduce treatment-related dysphagia based on each patient's sensitivity to radiotherapy. If successful, the results of Aims 2 and 3 wil be incorporated in the clinical study in later years. IMPACT: As DCE-MRI and DW-MRI are widely available in the community, the proposed studies will lead to future multi- institutional study which will assess the improvements in LR control rates and DFS in advanced HNC promised by the proposed concepts and investigations.